Clinical & Experimental Metastasis 

About: Clinical & Experimental Metastasis is an academic journal published by Springer Science+Business Media. The journal publishes majorly in the area(s): Metastasis & Cancer. It has an ISSN identifier of 0262-0898. Over the lifetime, 2404 publications have been published receiving 88817 citations.

The actin cytoskeleton in cancer cell motility.

Abstract: Cancer cell metastasis is a multi-stage process involving invasion into surrounding tissue, intravasation, transit in the blood or lymph, extravasation, and growth at a new site. Many of these steps require cell motility, which is driven by cycles of actin polymerization, cell adhesion and acto-myosin contraction. These processes have been studied in cancer cells in vitro for many years, often with seemingly contradictory results. The challenge now is to understand how the multitude of in vitro observations relates to the movement of cancer cells in living tumour tissue. In this review we will concentrate on actin protrusion and acto-myosin contraction. We will begin by presenting some general principles summarizing the widely-accepted mechanisms for the co-ordinated regulation of actin polymerization and contraction. We will then discuss more recent studies that investigate how experimental manipulation of actin dynamics affects cancer cell invasion in complex environments and in vivo.

Acidic pH enhances the invasive behavior of human melanoma cells.

Abstract: As a consequence of poor perfusion and elevated acid production, the extracellular pH (pHex) of tumors is generally acidic. Despite this, most in vitro experiments are still performed at the relatively alkaline pHex of 7.4. This is significant, because slight changes in pHex can have profound effects on cell phenotype. In this study we examined the effects of mildly acidic conditions on the in vitro invasive potential of two human melanoma cell lines: the highly invasive C8161, and poorly invasive A375P. We observed that culturing of either cell line at acidic pH (6.8) caused dramatic increases in both migration and invasion, as measured with the Membrane Invasion Culture System (MICS). This was not due to a direct effect of pH on the invasive machinery, since cells cultured at normal pH (7.4) and tested at acidic pH did not exhibit increased invasive potential. Similarly, cells cultured at acidic pH were more aggressive than control cells when tested at the same medium pH. These data indicate that culturing of cells at mildly acidic pH induces them to become more invasive. Since acid pH will affect the intracellular pH (pHin) and intracellular calcium ([Ca2+]in), we examined the effect of these parameters on invasion. While changes in [Ca2+]inwere not consistent with invasive potential, the changes in pHin were. While these conditions decrease the overall amount of gelatinases A and B secreted by these cells, there is a consistent and significant increase in the proportion of the activated form of gelatinase B.

Invadopodia: specialized cell structures for cancer invasion.

Abstract: The spread of cancer cells to distant sites in the body is the major cause of cancer patient death. Growing evidence connects specialized subcellular structures, invadopodia, to cancer invasion and metastasis. Invadopodia, or invasive foot processes, are actin-rich protrusions that localize matrix-degrading activity to cell-substratum contact points and represent sites where cell signaling, proteolytic, adhesive, cytoskeletal, and membrane trafficking pathways physically converge. Understanding how invadopodia form and function should aid in the identification of novel targets for anti-invasive therapy.

A novel orthotopic model of breast cancer metastasis to bone.

Abstract: Breast cancer affects approximately one woman in twelve and kills more women than any other cancer. If detected early, patients have a five year survival rate of 66%, but once metastatic disease has developed, there is no effective treatment. About 70% of patients with metastatic disease have bone involvement, while lungs and liver are the other common targets. Bone metastases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for metastatic breast carcinoma depends on a better understanding of the mechanism of homing of the tumour cells to bone, liver and lungs and the factors required for their growth in these organs. Research on mechanisms of breast cancer metastasis, particularly to bone, has relied on in vitro studies or on tumour models in which the inoculation route is designed to promote delivery of tumour cells to a specific organ. Metastases in bone are achieved by inoculation into the right ventricle of the heart. To our knowledge there has been no report of a model of metastatic spread from the mammary gland to distant sites which reliably includes bone. In this paper, we describe our recent development of a novel murine model of metastatic breast carcinoma. The new model is unique in that the pattern of metastatic spread closely resembles that observed in human breast cancer. In particular, these murine breast tumours metastasise to bone from the primary breast site and cause hypercalcaemia, characteristics not normally found in murine tumours, but common in human disease. Furthermore, in a preliminary characterisation of this model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correlates with metastasis to bone. This model therefore provides an excellent experimental system in which to investigate the factors that control metastatic spread of breast cancer to specific sites, particularly bone. The special advantage of this system is that it involves the whole metastasis process, beginning from the primary site. Existing models consider mechanisms that pertain to growth of tumour once the site has been reached. An understanding of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. For the first time, this development will allow exploration of the molecular basis of site-specific metastasis of breast cancer to bone in a clinically relevant model.

The role of proteolytic enzymes in cancer invasion and metastasis.

Abstract: The production of metastasis appears to involve a number of different proteases including the urokinase form of plasminogen activator, cathepsin B, cathepsin D and various metalloproteases. Early data implicating these proteases in metastasis were mostly indirect and based on correlation studies in animal models. More recent work, using specific protease inhibitors and antibodies against proteases to block experimental metastasis, have provided more direct evidence that proteases play a role in cancer spread. In addition, transfection of genes encoding certain proteases increases the metastatic phenotype of the recipient cells. In human tumours, a number of different proteases also correlate with metastatic potential. It is concluded that certain proteases may be new prognostic markers in cancer as well as new targets for anti-metastatic therapy.